1. Field of the Invention
This invention relates to an improved method for producing in high yields such dimeric alkaloids as vinblastine leurosidene, and 3',4'-anhydrovinblastine which are useful as antineoplastic drugs.
More specifically, this invention relates to a method for the production of a dimeric alkaloid, characterized by a procedure which comprises causing reaction of catharanthine with vindoline in the presence of Fe.sup.3+, then (1) removing or inactivating the Fe.sup.3+ and allowing a reducing agent to react on the resultant compound or (2) allowing the presence of oxygen and a dicarboxylic acid or a derivative thereof in the reaction system and then causing the resultant compound to react with a hydride source.
2. Description of the Prior Art
Such dimeric alkaloids as vinblastine and 3',4'-anhydrovinblastine have been known in the art as compounds possessing an antineoplastic activity (U.S. Pat. No. 4,029,663). As means of obtaining these compounds, methods which consist in extracting the compounds from a plant of genus Catharanthus, having the scientific name of Catharanthus roseous (alias Vinca rosea), and methods which resort to chemical synthesis using catharanthine and vindoline derived from the plant as starting materials have been known to the art.
The methods by extraction, however, entail difficulties in separation and purification of the dimeric alkaloids because the plant has a very small dimeric alkaloids content and also because a number of analogous compounds are additionally present in the plant.
Among the methods resorting to chemical synthesis, the method which comprises oxidizing catharanthine with a peracid, acylating the resultant N-oxide, causing reaction of the acylated product with vindoline and reducing the reaction product with NaBH.sub.4 (U.S. Pat. No. 4,144,237) has been known to the art.
The synthesis mentioned above, however, attains isolation of 3',4'-anhydrovinblastine only in a low yield of 41% and simultaneously gives rise to 10% of isomers as a by-product. Thus, this method entails difficulties in separation and purification of the dimeric alkaloids.